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PGx-Guided Dosing Can Lead to Faster Therapeutic Blood Levels of Antidepressants

NEW YORK — Using pharmacogenetics to guide initial dosing of tricyclic antidepressants may enable patients to accumulate therapeutic concentrations of the drugs in their blood faster than standard dosing schedules, a new randomized clinical trial has found.

Personalized dosing based on patients' cytochrome P450 genotypes was further associated with fewer and less severe adverse effects among patients with major depressive disorder (MDD). There were, though, no differences in depression symptom changes between patients dosed based on their CYP450 genotypes and those receiving usual care.

"I think our study [will] contribute to increased adoption of pharmacogenetic-informed dosing in MDD, but further steps are necessary," Joost Janzing, a psychiatrist at Radboud University Medical Center in the Netherlands and the senior author of a publication of the trial results appearing in JAMA Network Open on Monday, wrote in an email. 

Finding the correct dose of tricyclic antidepressants like nortriptyline, clomipramine, and imipramine for MDD patients typically requires multiple dose adjustments over a course of weeks. As CYP450 isoforms affect how patients metabolize antidepressants, basing patient dosage on their genotypes could improve effectiveness.

For the Pharmacogenetics for Individualized Tricyclic Antidepressant dosing study, a multicenter randomized controlled trial, the researchers recruited MDD patients whose psychiatrists considered them for tricyclic antidepressant treatment. All participants underwent CYP2D6 and CYP2C19 genotyping using established workflows at the participating institutes to establish whether they had a poor, intermediate, normal, or ultra-rapid metabolizer phenotype. Patients were then randomized to receive pharmacogenetics-informed treatment (PIT) based on their genotype and guidelines established by the Dutch Pharmacogenetics Working Group (DPWG) or usual care. In all, 56 participants were in the PIT arm and 55 in the usual care arm. There was a clinical follow-up time of seven weeks.

Patients in the PIT group reached a therapeutic plasma concentration five days faster than the control group, within a mean of 17.3 days versus 22 days. The PIT group further experienced fewer and less severe adverse effects.

"Based on our findings, we think that pharmacogenetic-informed dosing based on the DPWG guidelines can be considered," Janzing said.

However, the researchers found in a post hoc analysis that the faster times to therapeutic plasma levels they observed were largely driven by one drug: nortriptyline. Patients in the PIT group treated with nortriptyline reached a therapeutic plasma level in a mean of 13.4 days and a median of nine days. By contrast, patients in this dosing group treated with clomipramine or imipramine experienced more usual times to therapeutic plasma levels. For instance, those given clomipramine reached therapeutic plasma levels in a mean of 25.9 days.

This effect could be driven by differences in how the drugs are metabolized, according to the researchers. Nortriptyline metabolism, they noted, relies largely on CYP2D6, while clomipramine metabolism depends more on other CYP450 enzymes.

"The contribution of pharmacogenetic-informed dosing will probably depend on the kinetics of the drug, so further studies in other antidepressants are necessary," Janzing noted.

He and his colleagues also found that even though patients in the PIT group reached therapeutic plasma concentrations faster, this had no statistically significant effect on the reduction of their depression symptoms. The researchers suggested that this muted effect could in part be due to the characteristics of their overall cohort — patients in the study all had severe, chronic depression, which is known to be associated with limited treatment response. Many other factors, Janzing added, also affect symptoms of depression, including psychotherapy.

He and his colleagues plan to study additional drugs as well as examine multivariate models to predict therapeutic effects that additionally consider the contribution of other CYP enzymes and other pharmacodynamic-related genes.